Brief, high-frequency conditioning stimulation of the entorhinal afferents to the dentate gyrus produces long-term potentiation (LTP) of this monosynaptic response. It is now clear that a diversity of modifications exists, all of which may occur simultaneously, although to varying extents and at different, although adjacent, locations. The four long-term, associative modifications are excitatory synaptic potentiation, excitatory synaptic depression, and potentiation and depression of what may be disynaptically activated, inhibitory synapses mediating feedforward inhibition (or its functional equivalent). Our electrophysiological research seeks to determine the independence of these four phenomena, particularly the temporally associated conditions of pre- and postsynaptic activity/inactivity that lead to each modification. Anatomical studies seek the cellular bases of these diverse modifications. It appears that larger synapses correlate with excitatory synaptic potentiation. Fewer synapses may be associated with excitatory synaptic depression. A primary aim of this project is to dissociate the correlates of excitatory synaptic potentiation from synaptic depression and mere afferent activity during conditioning. The proposed research would characterize further the physiological and anatomical changes. We week: 1) to continue characterization and quantification of the ultrastructural correlates of the LTP-conditioning paradigm; 2) to define and distinguish the variety of modifications accompanying LTP and LTP-like conditioning paradigms; 3) to characterize the modifiability and to determine inferentially the role of granule cell dendritic spines and dendritic branching patterns as determinants of the spatiotemporal summation of inputs upon the granule cell; 4) to determine if the absolute number of synapses is altered with conditioning, and 5) to relate our work on modification as a function of use (associative activity/inactivity) to contemporary trends and problems in neuroscience. The methodologies employed include quantitative light and electron microscopy, stereology, electron microscopic autoradiography, light microscopic-Golgi methods, extracellular neurophysiology, and computer modeling of anatomical data. Understanding how synaptic connectivity can be altered in the adult brain and the cellular bases of these alterations should contribute to the development of rational treatments for brain injury due to disease, trauma, stroke, and aging.